title: Thrombin generation mediators and markers in sepsis-associated coagulopathy and their modulation by recombinant thrombomodulin.
abstract: Severe sepsis remains the most common cause of death in critically ill patients, and thrombin plays a crucial role in the pathogenesis of sepsis-associated disseminated intravascular coagulation (DIC). The purpose of this study was to profile prothrombin fragment (F1.2), thrombin-antithrombin complex (TAT), and d-dimer (DD) throughout the course of hospital stay in patients identified with sepsis. Plasma samples from patients enrolled in the ART-123 study, a phase 2b, international, multicenter, randomized placebo-controlled trial were analyzed for various parameters using enzyme-linked immunosorbent assay methods. Plasma levels of F1.2, DD, and TAT were measured at several time points following administration of recombinant thrombomodulin or placebo, and the results were tabulated. In the group treated with thrombomodulin, the median F1.2 levels demonstrated a 16% decrease from the baseline to day 7, while the placebo group showed an 8% increase. Both the treatment groups showed a gradual decrease in the TAT and DD, with the group treated with thrombomodulin demonstrating twice the decrease over the 7-day period. Although the data were widely scattered, these results show that DIC represents a hypercoagulable state along with other hemostatic abnormalities and the activation of the inflammatory process. Modulation of these activation processes through targets such as DD, F1.2, and TAT may play an important regulatory role in the pathogenesis of sepsis-associated coagulopathy. Moreover, this study validates the hypothesis that thrombomodulin downregulates the thrombin generation mediators/markers in sepsis-associated DIC.
authors.affiliation: 1Hemostasis & Thrombosis Research Laboratories, Loyola University Chicago, Maywood, IL, USA.
authors.forename: Debra
authors.initials: D
authors.lastname: Hoppensteadt
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Tsuruta
authors.forename: Josephine
authors.initials: J
authors.lastname: Cunanan
authors.forename: Joe
authors.initials: J
authors.lastname: Hirman
authors.forename: Inder
authors.initials: I
authors.lastname: Kaul
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Osawa
authors.forename: Jawed
authors.initials: J
authors.lastname: Fareed
mesh_terms: D000990:Antithrombin III; D015415:Biomarkers / Q000097:blood; D004211:Disseminated Intravascular Coagulation / Q000097:blood* / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D006801:Humans; D008297:Male; D010446:Peptide Fragments / Q000097:blood; D010447:Peptide Hydrolases / Q000097:blood; D011516:Prothrombin; D011994:Recombinant Proteins / Q000008:administration & dosage; D018805:Sepsis / Q000097:blood*; D013917:Thrombin / Q000096:biosynthesis*; D018180:Thrombomodulin / Q000008:administration & dosage*
chemical_list: C472045:ART123; D015415:Biomarkers; D005338:Fibrin Fibrinogen Degradation Products; D010446:Peptide Fragments; D011994:Recombinant Proteins; D018180:Thrombomodulin; C046193:antithrombin III-protease complex; C036309:fibrin fragment D; C045879:prothrombin fragment 1.2; D000990:Antithrombin III; D011516:Prothrombin; D010447:Peptide Hydrolases; D013917:Thrombin
keywords: disseminated intravascular coagulation; hypercoagulable; sepsis-associated coagulopathy; thrombomodulin